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Methamphetamine Administration Causes Death of Dopaminergic Neurons in the Mouse Olfactory Bulb

  • Xiaolin Deng
    Affiliations
    Molecular Neuropsychiatry Branch, Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
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  • Bruce Ladenheim
    Affiliations
    Molecular Neuropsychiatry Branch, Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
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  • Subramaniam Jayanthi
    Affiliations
    Molecular Neuropsychiatry Branch, Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
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  • Jean Lud Cadet
    Correspondence
    Address reprint requests to Jean Lud Cadet, M.D., Molecular Neuropsychiatry Branch, National Institute on Drug Abuse/IRP, 5500 Nathan Shock Drive, Baltimore MD 21224
    Affiliations
    Molecular Neuropsychiatry Branch, Department of Health and Human Services/National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland.
    Search for articles by this author
Published:December 11, 2006DOI:https://doi.org/10.1016/j.biopsych.2006.09.010

      Background

      Methamphetamine (METH) is an addictive drug that can cause neurological and psychiatric disorders. In the rodent brain, toxic doses of METH cause damage of dopaminergic terminals and apoptosis of nondopaminergic neurons. The olfactory bulb (OB) is a brain region that is rich with dopaminergic neurons and terminals.

      Methods

      Rats were given a single injection of METH (40 mg/kg) and sacrificed at various time points afterward. The toxic effects of this injection on the OB were assessed by measuring monoamine levels, tyrosine hydroxylase (TH) immunocytochemistry, terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate (dNTP) nick end labeling (TUNEL) histochemistry, and caspase-3 immunochemistry.

      Results

      Methamphetamine administration caused marked decreases in dopamine (DA) levels and TH-like immunostaining in the mouse OB. The drug also caused increases in TUNEL-labeled OB neurons, some of which were also positive for TH expression. Moreover, there was METH-induced expression of activated caspase-3 in TH-positive cells. Finally, the METH injection was associated with increased expression of the proapoptotic proteins, Bax and Bid, but with decreased expression of the antideath protein, Bcl2.

      Conclusions

      These observations show, for the first time, that METH can cause loss of OB DA terminals and death of DA neurons, in part, via mechanisms that are akin to an apoptotic process.

      Key Words

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